Tolerance to self major histocompatibility (MHC) antigens occurs during T cell maturation in the thymus. During ontogeny, exposure of the immune system to MHC antigens results in the loss of reactivity to those antigens, thus leaving the animal specifically tolerant into adult life. Inducing tolerance in adult animals has been accomplished by high-dose cytoreductive therapy and bone marrow transplantation.
Bone marrow transplantation has been found to be effective in the control of certain malignant lymphohematopoietic diseases where conventional chemotherapy has failed or would be expected to fail. There are attendant disadvantages to bone marrow transplantation. Often there is an allogeneic antitumor effect independent of the chemoradiotherapy of the preparative regimen. This adoptive immunotherapy effect is, in large measure, accompanied by graft-versus-host (GVH) disease.
Historically, GVH disease has been a major cause of serious morbidity and death after bone marrow transplantation. Graft-versus-host disease and its treatment are accompanied by profound immunodeficiency and immune dysregulation, which places the patient at risk for life-threatening infections and other complications. GVH disease has accounted for approximately two thirds of the deaths after allogeneic bone marrow transplantation.
Removing T lymphocytes in allogeneic bone marrow inocula to prevent GVH disease is associated with increased rates of engraftment failure. While these drawbacks are generally considered acceptable for the treatment of otherwise lethal malignant diseases, they would severely limit the application of MHC mismatched bone marrow transplantation as a preparative regimen for organ transplantation, in which nonspecific immunosuppressive agents, while not without major complications, are effective.
Since GVH disease is immunologically mediated, efforts to prevent its development have involved the use of immunosuppressive therapy. Of the many agents studied, methotrexate, glucocorticoids, and cyclosporin have been found to be useful. It is a continuing goal to develop better treatments for patients in need of a bone marrow transplant or other diseases that can be specifically cell targeted.